Recent major discoveries in the genetics of frontotemporal lobar degeneration (FTLD) have accelerated the understanding of the pathogenetic mechanisms underlying FTLD and related disorders. These include the discovery of mutations in progranulin (GRN) as an important cause of FTLD and the finding of TAR DNA binding protein 43 (TDP43/TARDBP) as a major component of the intraneuronal inclusions in FTLD. Over the past years, the Genetics Core has 1) screened a significant number of PPG patients for mutations in known genes causing dementia (including MAPT), identifying known and novel mutations and a novel risk factor for neurodegeneration; 2) characterized the genotype for most of the known risk factors for dementia, including APOE and MAPT haplotypes; and 3) started a productive collaboration with the laboratory of Rosa Rademakers at Mayo Clinic Jacksonville, a leading group in the study of FTD genetics. We will continue to collect DNA and RNA from peripheral blood from patients and controls with FTD-spectrum disorders evaluated through the PPG, and to screen select cases for mutation in all the dementia-causing genes. Indepth analysis of peripheral progranulin level will be performed in collaboration with the Rademakers lab.Cell lines will be created and stored in the NIH-funded AD National Cell Repository. We will also assess a panel of common polymorphisms in several genes that have been reported to modulate the dementia risk, memory performance, or social behavior, RNA from peripheral blood will be collected and used for gene expression studies. Finally, we propose to identify new loci associated with FTD and AD using novel mapping methods. These genetic data will be integrated with clinical, pathological and imaging data to achieve the core aims of the PPG projects, which are advancing our understanding of the diagnosis, characterization, and genetic architecture of neurodegenerative dementia and, in conjunction with the other sections of the current Program Project, building an extremely well characterized series of patients with neurodegenerative dementia and controls, a potentially invaluable resource for the field.